Alzheimer's disease (AD), the most common dementing disorder, is characterized by senile plaques, neurofibrillary tangles, and loss of synapses and neurons in the brain. The predominant proteinaceous component of the senile plaques is β-amyloid peptide (Aβ), which is produced by proteolytic cleavage of its precursor, the β-amyloid precursor protein (APP). The amyloid hypothesis states that Aβ initiates the cascade of events that results in AD. The precise mechanism of amyloid toxicity is unclear, but evidence has been accumulating that the synapse is an early vulnerable site for Aβ damage (see, for example, Selkoe, D. J. in Science 298:789-91(2002)). Consistent with this idea, some APP transgenic mice with high levels of Aβ in the brain show synapse loss, behavioral changes, and reductions in synaptic transmission prior to the formation of senile plaques (see Hsia, A. Y. et al. in Proc Natl Acad Sci USA 96:3228-33 (1999) and Mucke et al., in J. Neurosci. 20:4050-8 (2000)). Recently, it has been shown that APP is also cleaved at Asp664 (APP695 numbering) by caspases, the cysteine proteases that mediate apoptosis (see Gervais, F. G. et al. in Cell 97:395-406 (1999) and Lu, D. C. et al. in Nat Med 6:397-404 (2000)). Such processing liberates a cytotoxic carboxyterminal peptide, APP-C31; however, the role (if any) that caspase processing of APP may play in AD is unknown. This generation of a cytotoxic peptide following intracytoplasmic cleavage by caspases is similar to what has been shown to occur for dependence receptors such as DCC (deleted in colorectal cancer), RET (rearranged during transfection) and UNC5H1-3 (uncoordinated gene 5 homologues 1-3), suggesting that APP may function as a dependence receptor (Bredesen et al., Physiological Reviews, in press 2004).
Accordingly, development of transgenic models that allow investigation into the role that proteases, such as caspases, play in the development of such neurodegenerative diseases as Alzheimer's disease, would be of great interest. In addition, the availability of such transgenic models would facilitate development of new treatments for neurodegenerative diseases.